Glutamate is a major excitatory transmitter in the central nervous system and is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation. In the case of the NMDA receptor, the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time. Thus, glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
Therefore, glycine B antagonists, such as glycine B antagonists restricted to action in the peripheral nervous system (PNS), may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia;
chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration;neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children;drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse;skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis;diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation;diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS);eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration;diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease;migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
A number of quinoline derivatives have been previously described.
U.S. Pat. No. 7,084,156 discloses 2-aminoquinolines of general formula (I) as melanin concentrating hormone receptor antagonists:
wherein R1 and R2 represent, e.g., hydrogen, C1-6alkyl, cycloalkyl, heterocycloalkyl, aryl (wherein these groups may be further substituted); R3 represents e.g., hydrogen, halogen, C1-8alkyl, perfluoroC1-6alkyl, cycloalkyl, aryl, heteroaryl, OR7, NR7R7, CO2R7 (wherein R7 represents, e.g., hydrogen, C1-6alkyl, aryl, heteroaryl, cycloalkyl); R4 represents, e.g., hydrogen, halogen, C1-6alkyl, trifluoromethyl, cycloalkyl, OR7, NR7R7, CO2R7; R5 represents, e.g., hydrogen, halogen, C1-6alkyl, perfluoroC1-6alkyl, OR7, NR7R7; and R6 represents, e.g., —(CH2)n—R7, —(CH2)n-aryl-R7, —(CH2)n-heteroaryl-R7, —(CH2)n—NR7C(O)—R7, —(CH2)n—N(R7)2—R7, wherein n represents 0 to 5 and wherein the hydrogen atoms of the (CH2)n moiety may be further substituted.
U.S. Pat. No. 7,087,758 discloses quinoline compounds of general formula (I) as inhibitors of hYAK1 and hYAK3 kinases:
wherein R1 represents, e.g., NH—C1-6alkyl, NH—C3-7cycloalkyl, NH-aryl, NH-Het (wherein these groups may be further substituted); R2 represents, e.g., CO2H, CONH2, CHNOH; R3 represents, e.g., H, OH, C1-6alkyl, halogen; R4 represents, e.g., H, C1-6alkyl, C3-7cycloalkyl, halogen; R5 represents H or halogen.
US Published Application No. 2006/0106058 discloses 3-carboxy quinoline derivatives of general formula (I) as YAK3 inhibitors:
wherein R1 represents H or C1-C6alkyl; R2 represents (Q)q-(Q′)r-(Q2), wherein Q represents CH2, q represents 0-4, Q′ represents O, NH, or CHOH, r represents 0 or 1, and Q2 represents, H, C1-C6alkyl, aryl, heterocyclic, C3-C7cycloalkyl, C(O)ORb (wherein Rb represents H, or C2-C4alkenyl), or NRbRb, or heteroaryl, wherein Q2 may be further substituted; R3 and R3a represent H or C1-C6alkyl, or may combine to form a ring; m and n represent 0 or 1; R4 represents OH, NH(SO2)Rc, or NRb(R) (wherein Rc represents aryl or C1-C6alkyl); and R5 represents H or halogen.
US Published Application No. 2007/0197509 discloses compounds of general Formula (2) as modulators of gated ion channel activity:
wherein R1, R3, and R4 represent, e.g., hydrogen, optionally substituted amino, cyano, nitro, CO2H, amide, halogen, R2 represents, e.g., hydrogen, optional substituted amino, amide, halogen, CO2X1 (wherein X1 represents hydrogen, C1-6alkyl, amino, or optionally substituted aryl) as well as more complex substituents, and R5 represents N, C, or CH.
U.S. Pat. No. 7,109,212 discloses quinoline and isoquinoline derivatives of general formula (I) as inflammation inhibitors:
wherein A represents optionally substituted aryl, benzyl, or phenethyl; R1 and R2 represent hydrogen, methy, or ethyl or combine to form a ring; R3 represents C1-3alkyl optionally substituted by fluorine, B represents methylene (optionally substituted by methyl or ethyl) or carbonyl; and Q represents an optionally substituted quinolinyl or isoquinolinyl group.
International Publication No. WO 02/26713 discloses antiparasitic compounds of general Formula (I):
wherein R2-R8 represent, e.g., hydrogen, C1-C20alkyl, C6-C15aryl, halo, NR10R11, COOR10 (wherein R10 and R11 represent hydrogen, optionally substituted C1-C20alkyl, and optionally substituted C6-C15aryl).
U.S. Pat. No. 4,962,203 discloses compounds of general Formula I as selective antagonists of leukotrienes of D4:
wherein R1 represents, e.g., H, halogen, C1-C8alkyl, OR2, NR2R2, COOR2, NO2 (wherein R2 represents, e.g., H, C1-C8alkyl); R3 represents -(A)m-(CR2═CR2)p—(CR2R2)m-Q; A represents CR2R4 or C═O; Q represents, e.g., COOR2, tetrazole; R4 represents, e.g., H, halogen, NO2; Y represents e.g., (CR2═CR2)n, —X—CR2R2, —CR2R2—X; m represents 0-8; n represents 1-2; and p represents 0-2.
U.S. Pat. No. 5,801,180 discloses compounds of general formula (1) as useful in treating various ischemic heart diseases:
wherein ring A represents a benzene ring, a pyridine ring, or a cyclohexane ring; ring B represents a pyridine ring, a pyrimidine ring, or an imidazole ring; R1-R4 represent, e.g., hydrogen, halogen, lower alkyl optionally substituted by halogen, lower alkoxy, acylamino, carboxy, NR45R46 (wherein R45 and R46 represent hydrogen or lower alkyl or combine to form a ring); R5 represents, e.g., hydrogen, halogen, hydroxyl, hydrazino, lower alkyl, carboxyl; R6 represents, e.g., hydrogen, halogen, hydroxyl, amino, lower alkyl, —N(R17)—Y—R18 (wherein R17 represents hydrogen, lower alkyl, acyl, lower alkoxyalkyl, carboxyalkyl, or hydroxyalkyl, Y represents (CH2)q (wherein q represents 1 to 8, and wherein the CH2 group may be substituted) and R18 represents hydrogen, hydroxyl, carboxyl, cyano, optionally substituted heteroaryl, or optionally substituted cycloalkyl.